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Pharmacology II
Respiratory Pharmacology
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"Respiratory Pharmacology

Dilates the bronchi and inhibits mediator release
Smooth muscle relaxant
Increase 3,5-Cyclic AMP in mast cells and eosinophils by:
   Activating adenylate cyclase
Increases the level of c-AMP, from ATP
       ATP ® ­ c-AMP
Promotes the release of heparin from mast cells, an anti-inflammatory molecule
   -Limits the recruitment of eosinophils into the airway
   -Limits damage to the mucosa
Inhibit mast cell degranulation
   -Modifies the Early asthmatic response
Inhibit arachidonic aacid metabolite sysnthesis (bronchoconstrictor)
Block the release of:

Postive feedback is quick, compared to slower anti-inflammatory group drugs
The 1st line drugs for rescue treatment of acute asthma symptoms in all age groups
Most potent/rapid acting bronchodilators in use today
   -Bronchodilation is maximal after 30 minutes
   -Duration is about 3-4 hours

   Asthma control may deteriorate if only b -2 are used without anti-inflammatory agents. May allow:
      -Chronic inflammation of airway wall
      -Permanent airway narrowing
   May worsen asthma by increasing tolerance (tachyphylaxis) to the agonists
   May inhibit the action of glucocorticoids
   May ­ risk of death if usage is > 1 canister/month

b 2 Adrenergic Agonist usage
   Episodic asthma…use b -agonists as sole therapy
   Chronic asthma…use b -agonists along with anti-inflammatory drugs
   Rescue situations…use the combination
   Nocturnal asthma…not effective
   Not contraindicated in the pre and postoperative periods

Albuterol (Proventil, Ventolin, Volmax, Airet)
Beta2-Adrenergic Agonist

Use: Bronchodilator in reversible airway obstruction due to asthma or COPD
Mechanism of action: Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on heart rate.
   Peak effect:   
      Oral: 2-3 hours
      Nebulization/oral inhalation: Within 0.5-2 hours
   Duration of action:
      Oral: 4-6 hours
      Nebulization/oral inhalation: 3-4 hours
Metabolism: By the liver to an inactive sulfate, with 28% appearing in the urine as unchanged
   Inhalation: 3.8 hours
   Oral: 2.7-5 hours
Elimination: 30% appears in urine as unchanged drug
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 39
Adverse Reactions: > 10%
   Cardiovascular: tachycardia, palpitations, pounding heartbeat
   Gastrointestinal: GI upset, nausea
Drug interactions:
Decreased effect with concomitant beta-adrenergic blockers (eg, propranolol), digoxin serum
      levels may be decreased
   Increased therapeutic effect: Inhaled Atrovent may increase duration of bronchodilation,
      Nifedipine may increase FEV-1
   Increased toxcity: CV effects may be potentiated in patients already receiving MAO inhibitors,
      tricyclic antidepressants; concomitant administration of sympathomimetic agents (eg,
      amphetamine, dopamine, dobutamine) may result in enhanced CV effects, inhaled
      anesthetics (eg, enflurane)

Bitolterol (Tornalate)
Beta2-Adrenergic Agonist

Use: Prevention and treatment of bronchial asthma and bronchospasm
Mechanism of action: Selectively stimulates beta2-adrenergic receptors in the lungs producing bronchial
   smooth muscle relaxation; minor beta1 activity
   Onset of action: 3-5 min
   Duration of effect: 4-8 hours
   Metabolism: Is a prodrug, is hydolyzed to colterol (active) following inhalation
   Half-life: 3 hours
   Time to peak serum concentration (colterol): Inhalation: Within 1 hour
   Elimination: In urine and feces
Usual dosage: Children > 12 years and Adults:
   Bronchospasm: 2 inhalations at an interval of at least 1-3 minutes, followed by a third inhalation
      if needed.
Adverse Reactions: > 10%
   Neuromuscular & skeletal: Trembling
Drug interactions:
   Decreased effect: Beta-adrenergic blockers (eg, propranolol)
   Increased effect: Inhaled Atrovent may increase duration of bronchodilation, nifedipine
      may increase FEV-1
   Increased toxcity: MAO inhibitors, tricyclic antidepressants, sympathomimetic agents,
      inhaled anesthetics (enflurane)

Epinephrine (Adrenalin, Sus-phrine,Bronkaid, AsthmaNefrin, Racemic Epinephrine, etc)
Adrenergic Agonist Cardivascular: ­ CO, ¯ TPR, ­ mean BP, ¯ renal perfusion
Adrenergic Agonist Agent

Uses: Treatment of bronchospasms, anaphylactic reactions, cardiac arrest, management of open-angle
   glaucoma; added to local anesthestics to decrease systemic absorption, increase duration of action,
   and decrease toxcity of the local anesthetic
Mechanism of action: Stimulates alpha-, beta1-, and beta2-adrenergic receptors resulting in relaxation of
   Smooth muscle of the bronchial tree, cardiac stimulation, and dilation of skeletal muscle
   Vasculature; small doses produce can cause vasodilation via beta2-vascular receptors; large doses
   May produce constriction of skeletal and vascular smooth muscle; decreases production of
   Aqueous humor and increases aqueous outflow; dilates the pupil by contracting dilator muscle
   Onset of bronchodilation:
      Subcutaneous: Within 5-10 minutes
      Inhalation: Within 1 minute
   Metabolism: Following administration, drug is taken up into the adrenergic neuron and
      metabolized by monoamine oxidase and catechol-o-methyl-transferase; circulating
      drug is metabolized in the liver.
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 329-330
Adverse Reactions: > 10%:
   Cardiovascular: Tachycardia (parenteral), pounding heartbeat
   CNS: Nervousness, restlessness
Drug Interactions:
   Increased toxcity: Increased cardiac irritability if administered concurrently with halogenated
      inhalational anesthetics, beta-blocking agents, alpha-blocking agents


Levalbuterol (Sepracor)

Isoetharine (Bronkometer)

Isoproterenol (Isuprel, Mistometer, Medihaler-iso, Norisodrine)
Adrenergic Agonist Agent

Use: Parentrally in ventricular arrhythmias due to A-V nodal block; hemodynamically compromised
   Bradyarrthythmias or atropine-resistant bradyarrthymias; temporary use in third degree A-V block
   until pacemaker insertion; low cardiac output; vasoconstrictive shock states; treatment of
   reversible airway obstruction as in asthma or COPD
Mechanism of action: Stimulates beta1- and beta2 receptors resulting in relaxation of bronchial, GI, and uterine smooth muscle, increased heart rate and contractility, vasodilation of peripheral vasculature
   Onset of bronchodilation:
      IV: immediate
   Metabolism: By conjugation in many tissues including the liver and lungs
   Half-life: 2.5 5 minutes
   Elimination: In urine principally as sulfate conjugates
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 505
Adverse Reactions: > 10%
   CNS: Insomnia, restlessness
   GI: Discoloration of saliva (pinkish-red), xerostomia, dry throat
Drug Interactions:
   Decreased effect with beta-blockers
   Increased pressor effects with sympathomimetics, albuterol, guanethidine, oxytocic agents, TCAs
   Arrythmias with bretylium, theophylline

Metaproterenol (Alupent, Metaprel)
Beta2-Adrenergic Agonist Agent

Use: Bronchodilator in reversible airway obstruction due to asthma or COPD; because of its delayed onset
   of action (1 hour) and prolonged effect (4 or more hours), this may not be the drug of choice for
   assessing response to a bronchodilator.
Mechanism of action: Beta1- and beta2-adrenergic stimulation; relaxes bronchial smooth muscle by action on beta2 receptors with very little effect on heart rate.
      Onset of bronchodilation: Within 15 min
      Peak effect: Within 1 hour
      Duration of action: ~ 1-5 hours
      Onset of effects: within 60 seconds
      Duration of action: Similar (~ 1-5 hours) regardless of route adminstered
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 589
Adverse reactions: > 10%
   CNS: Nervousness
   Neuromuscular & skeletal: Tremor
Drug interactions:
   Decreased effect: Beta-blockers
   Increased toxcity: Sympathomimetics, TCAs, MAO Inhibitors

Pirbuterol Acetate (Maxair, Autohaler)

Salmeterol Xinafoate (Serevent)
Adrenergic Agonist Agent
Beta2-Adrenergic Agonist Agent

Use: Maintainence and treatment of asthma and in prevention of bronchospasm in patients > 12 years of
age with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting beta2 agonists; prevention of exercise-induced bronchospasm. Not recommended for acute treatment of bronchospasm.
Mechanism of action: Relaxes bronchial smooth muscle by selective action on beta2 receptors with little
   Effect on heart rate; also inhibits release of inflammatory mediators from the lung; because
   salmeterol acts locally in the lung, therapeutic effect is not predicted by plasma levels.


   Onset of action: 5-20 minutes (average 10 minutes)
   Peak effect: 2-4 hours
   Duration: 12 hours
   Protein binding: 94% to 98%
   Metabolism: Hydroxylated in liver
   Half-life: 3-4 hours
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 851
Adverse reactions: > 10%
   CNS: Headache
   Respiratory: Pharyngitis
Drug interactions: CYP3A3/4 enzyme substrate
   Increased effect: Beta-adrenergic blockers (eg, propranolol)
   Decreased toxcity (cardiovascular): MAO inhibitors, tricyclic antidepressants

Terbutaline Sulfate
(Brethaire, Brethine, Bricanyl)
Beta2-Adrenergic Agonist Agent
Tocolytic agent

Use: Bronchodilator in reversible airway obstruction and bronchial asthma; inhibition of premature
   labor (oral and IV)
Mechanism of action: Selective B2 agonist that relaxes bronchial smooth muscle and peripheral vessels
   Onset of action:
      Oral: 30-60 min
      SC: within 6-15 min
      Oral inhalation: 5-30 minutes
   Peak effect:
      Oral: 2-3 hours
      SC: 30-60 min
      Oral inhalation: 1-2 hours
   Protein binding: 25%
   Metabolism: In the liver to inactivate sulfate conjugates
   Bioavailability: SC doses are more bioavailable than oral
   Half-life: 11-16 hours
   Elimination: In urine
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 912
Adverse reactions: > 10%
   CNS: Nervousness, restlessness
   Neuromuscular & skeletal: trembling
Drug interactions:
Decreased effect with beta-blockers
   Increased toxcity with MAO inhibitors, TCAs

a - and b - site/selectivity      
         a 1   a 2   b 1   b 2   
TERBUTALINE      -   -   -   +
ABUTEROL      -   -   -   +
EPHEDRINE      +   +   +   +
METAPROTERENOL   -   -   -   +
ISOETHARINE      -   -   -   +
EPINEPHRINE      +   +   +   +
ISOPROTERENOL   -   -   +   +   

Reactive airway
New Pathogenesis:
The precise nature of the inflammatory response in asthma has not yet been defined…
Chronic inflammatory disease of the airways
Inflammatory reactions ® smooth muscle contraction, swelling of the airway, mucous secretions, structural changes
      Becomes chronic if not treated appropriately
Autonomic abnormality:
      Disruption of the bronchoconstrictor-bronchodilator balance-tone imbalance
      Excitatory vs inhibitory stability is altered
Complex interactions between inflammatory mediators and effector cells:
      Leukotrienes…very potent (upper and lower airway)

Key cellular players in asthma
   Central role in seasonal/intermittent asthma:
   Mast cells
   Eosinophils…major inflammatory cell in the airway mucosa

   In severe, steroid dependent asthma:

Origin of Asthma
Anytime…any age

If present in childhood, peak prevalence…6 to 11 years of age
Diagnosis is confirmed by treating with b 2-agonists for 5 to 10 days

Classification/precipitants of Asthma
Allergen induced:
      Associated with allergic rhinitis

Inhaled or ingested:
      Antigens, irritants, metabolites
      Reflux of gastric fluid into the lower esophagus
Drug induced:
      Aspirin or Non-steroidals
Strenuous exercise
      Upper respiratory tract infections
Adenylcyclase deficiencies:
      Increases cyclic AMP…bronchodilator
      Cold may evoke symptoms

Signs and Symptoms of Asthma
   Symptoms appear with:
      Airflow limitation
      Increased airway responsiveness to stimuli
      66% do not wheeze when they are obstructed
      - Concentric bronchoconstriction…no turbulent flow
      Secretions may cause turbulence
      Correlates with the degree of expiratory airflow obstruction

Optimizing the Asthmatic
   FEV1 measurement is the "gold standard"
      -80% of predicted
      -20% increase is expected after bronchodilator use
   Eosinophil count:
      Parallels the degree of:
      -Hyper reactivity
   Steroid therapy is provided according to the results
      -3 day pretreatment regimen for scheduled surgery is beneficial
   Patients are experts about themselves…and their condition
   Patient’s knowledge base…some better than others:
      -Bronchodilators…acute situations…symptom relievers

   Economic, cultural, pharmaceutical influences play a role

   Aerosol delivery and deposition
      Developed in 1950’s
      Attempts to deliver to lower airways vs upper
      Mass median aerodynamic diameter (MMAD)
      -Particle size is best between 1-5m m

   Available delivery systems:
   Delivery device….particle size
   Jet nebulizers…….3-8m m
   Metered dose…….1-4m m
   Ultrasonic nebulizers (home/portable use)
   Dry powder inhalers

   -Permit aerosol to "mature"…big droplets fall out
   -Slow the flow…less deposition in large airways
   -Minimize "cold Freon" effect…evaporation of Freon
   -Serve as reservoir for meds

Aerosolized medications
   Anesthetics…usually 4% Lidocaine
   Bronchodilators…b -agonists
   Others (See Handout)

Aerosol Advantages vs Systemic
   Specific to the site of action…minimal systemic side effects
   Smaller doses needed
   More effective drug response
   -averts the 1st pass effect
   Rapid therapeutic onset of action

Aerosol disadvantages
   Shorter duration of action in acute asthma
   Mastering technique is difficult
   -Insufficient knowledge
   -Lack of control over delivery variables
   Unsupervised…and self medicated

Factors affecting aerosol delivery and deposition
   Particle size-optimal size is 4m m
      -5-10m m--------first 6 airway generations
      -2-5m m---------proximal alveolar deposition
      -1-2m m---------alveoli with 95-100% deposition
   80-90%-------------------deposited in mouth and pharynx
   10%-----------------------reaches site of action
   Inertial impaction…WARP 10…can’t get around corners
      >5m m-----impact against:
      -Lateral walls of the first few bronchial generations
   ­ Gravitational sedimentation with:
      -Reduced particle velocity and slow airflow
   Airway configuration
      -Wide diameter: less premature impaction
         Better delivery in males…more difficult in females and children
   -50% of patient population are technique handicapped
   Inspiratory hold or expiratory pause
   -5-10 seconds is better

Treatment of Asthmatics
      -Beta-2 agonists…drugs of choice in acute asthma
   Anti-inflammatory Drugs

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Last Updated 04/10/00 12:26:57 PM
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